1. Field of the Invention
The invention generally concerns the field of immunology, and more specifically concerns the treatment of autoimmune and inflammatory disease. Proteinaceous compositions described herein may be used as enteral therapeutics for the treatment or prevention of autoimmune and inflammatory disorders.
2. Description of Related Art
Autoimmune and disease result when an immune system of a subject mounts a response against the subject's own cells or proteins. In part because of the chronic nature of these diseases, effective treatment has proved difficult. One model system that is widely used in the study of autoimmune disease is the experimental autoimmune encephalomyelitis (EAE) model. EAE is a T cell mediated inflammatory autoimmune process of the central nervous system (CNS) that resembles the human demyelinating disease multiple sclerosis (MS) (Alvord et al., 1965). This model provides a useful animal system for the evaluation of potential therapies for human autoimmune and disease (Raine et al., 1977; Wisnewski & Keith 1977; Feuer et al., 1985). Previous studies using the EAE model have demonstrated that immunoactive proteins such as type I interferon administered orally (ingested) can inhibit clinical attacks in acute rat EAE and suppresses clinical relapse and inflammation in murine chronic relapsing EAE (U.S. patent application Ser. No. 08/844,731; Brod & Burns 1994; Brod et al., 1995).
Alpha-melanocyte stimulating hormone (MSH) is a short amino acid hormone that is processed in vivo from the hormonal precursor proteins proopiomelanocortin (POMC) and adrenocorticotropic hormone (ACTH). The purification and activation of alpha-MSH precursors, such as ACTH has been previously described in U.S. Pat. Nos. 2,904,471 and 2,992,165. Furthermore, synthetic analogs of alpha-MSH have been developed as therapeutics and imaging agents for use in a variety of diseases (U.S. Pat. No. 6,338,834). However, it is not clear whether such analogs maintain the full repertoire of therapeutic functionality possessed by intact alpha-MSH polypeptides.
Alpha-MSH itself immono-modulates inflammation via melanocortin receptor (MC-1R)-expressing monocytes, macrophages, and dendritic cells (DCs) (Luger et al., 2003) and via primed regulatory (MC5r)-expressing antigen-specific CD25+ CD4+ Treg cells (Tayor et al., 2001; Taylor 2003). Interestingly, alpha-MSH generated autoantigen-specific Treg cells can adoptively transfer protection against autoimmunity (Namba et al, 2002), significantly impair TNF-α-induced lymphocyte adhesion and cell adhesion molecules (CAMs) E-selectin, VCAM-1, and ICAM-1 (Scholzen et al., 2003) and DTH (Taylor et al., 2000). Crude ACTH formulations such as those described in PCT Appln. WO2006/021814 may be used to treat a variety of autoimmune diseases and cancers. Also, U.S. Pat. No. 4,874,744 concerns alpha-MSH formulations for treating dermatitis. More recently, U.S. Pat. No. 7,169,603 described alpha-MSH concatamers and their use in treating a variety of disease states. Nonetheless, methods for effective treatment of autoimmune diseases by enteral administration of alpha-MSH have not previously been described. In fact, previous studies seemed to indicate that alpha-MSH may not be active when administered orally (Van der Zee et al., 1988).